Non-thrombogenic devices for treating edema

ABSTRACT

The invention provides intravascular devices for treating certain medical conditions such as edema without causing thrombosis. The intravascular devices of the disclosure include non-thrombogenic surfaces that improve blood compatibility by reducing device-related thrombus formation and inflammatory reactions. The non-thrombogenic surfaces may include surface topographies (e.g., surface roughness) and modified chemistries (e.g., coatings and/or treatments), which prevent thrombosis by reducing local shear forces and inhibiting adhesion of blood clotting factors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication No. 63/036,145, which was filed on Jun. 8, 2020, thecontents of which are incorporated by reference.

TECHNICAL FIELD

This disclosure relates to devices for treating edema.

BACKGROUND

Congestive heart failure occurs when the heart is too weak to pump bloodproperly. As a result, blood pressure increases in the veins. Theincreased blood pressure prevents the lymphatic system from drainingfluid from surrounding tissue leading to an abnormal buildup of fluid.The abnormal buildup of fluid manifests as swollen or puffy skin and isknown as edema. If untreated, edema may lead to difficulty breathing(dyspnea) and in some cases acute decompensated heart failure (ADHF).

Some attempts to treat edema have involved the use of catheters that areplaced in a blood vessel and used to drain lymphatic fluid from thetissues. Unfortunately, like many devices placed in the bloodstream,intravascular catheters are susceptible to problems. Blood forms clotson the surfaces of devices placed into the bloodstream. As a clot buildsup, it blocks, or occludes, the catheter and even the entire vesselitself. Such occlusions may stop the flow of blood and cause cathetermalfunctions. Due to that blood clotting, also known as thrombosis, theuse of intravascular catheters faces significant complications.

SUMMARY

This disclosure provides intravascular devices, e.g., indwellingcatheters, that may reside in the vasculature or other bodily lumens ofpatients without causing blood clots. To prevent blood clots, thedisclosure provides surface treatments, materials, modifications, andchemistries that inhibit the formation of blood clots and are thusnon-thrombogenic. In particular, intravascular devices of the disclosurehave non-thrombogenic surfaces that inhibit activation of blood defensemechanisms and adherence of blood clotting factors. The non-thrombogenicsurfaces may include specific surface topographies (e.g., surfaceroughness) or modified surface chemistries (e.g. coatings or treatments)that improve biocompatibility of the intravascular device. Moreover,intravascular devices of the disclosure may include certain shapes thatpromote fluid flow patterns through the device with minimal disturbancesthereby reducing shear forces otherwise associated with thrombosis.

In one aspect, the invention provides an intravascular device comprisinga catheter that is dimensioned for insertion into a vein. The cathetercomprises a proximal portion and a distal portion with a cage attachedto the distal portion. The cage housing an impeller. At least a portionof the cage or the impeller comprises a modified surface chemistry(e.g., a coating or a treatment) that minimizes or prevents formation ofblood clots. In preferred embodiments, both the cage and the impellercomprise the modified surface chemistry. And preferably, substantiallyall of the cage and/or the impeller that is exposed to blood when thecatheter is operating inside the vein comprises the modified surfacechemistry.

The modified surface chemistry may provide a hydrophilic surface. Thehydrophilic surface may prevent blood clots by allowing blood water tooutcompete blood proteins, e.g., circulating blood clotting factors, foradhesion with the hydrophilic surface. As such, surfaces of theinvention may prevent thrombosis on account of providing one or morehydrophilic surfaces that preferentially adhere with water molecules andthereby reduce plasma protein adherence on the hydrophilic surface. Insome embodiments, when the catheter is inserted into the vein, thehydrophilic surface creates a layer of water molecules on thehydrophilic surface, thereby creating a barrier to plasma proteinadherence by, for example, reducing or eliminating the number of bindingsites for blood platelet adhesion to the hydrophilic surface.

In some embodiments, the modified surface chemistry comprises a coating.The coating may be applied to the cage or the impeller; preferably both.The coating may comprise one or more of a polysaccharide, a polymer, ora hydrogel. For example, the coating may comprise the polysaccharideheparin. Heparin may provide the surface with an affinity forantithrombin. The presences of antithrombin on surfaces of the cathetermay prevent blood clots by inactivating enzymes associated with theblood coagulation system.

In certain embodiments, the coating may comprise a thickness and thecoating thickness may be greater than a surface texture (e.g.,roughness) of the catheter. In some embodiments, the modified surfacechemistry follows the contours and the roughness of the cage or theimpeller. Where the modified surface chemistry creates a barrier ofwater when the catheter is inserted inside a vein, the layer of watermay comprise a thickness that is greater than an average (Ra) of asurface of the cage or the impeller. The coating may comprise one of apolyurethane, polyethylene glycol, poly-2-oxazolines, polyvinyl alcohol,polyvinylpyrrolidone, maleic anhydride copolymer,poly(lactide-co-glycolide), aminoalkyl (meth)acrylamide,aminopropylmethacrylamide, poly-phosphorylcholine, polyethylene oxide,polyethylene succinate, polyethylene adipate, polyvinylalcohol-co-ethylene, polyacrylic acid, copolymers and blends thereof.The coating may further comprise one of polyethyleneimine, a sulfonategroup, albumin, a polyamine, polyvinyl siloxane, hyaluronic acid, or anycombination thereof.

In preferred embodiments, at least one of the cage or the impellercomprises a metal having the modified surface chemistry. The metal maycomprise one of scandium, titanium, vanadium, chromium, manganese, iron,cobalt, nickel, copper, or zinc. The modified surface chemistry mayinclude a modification to an oxide layer of cage or the impeller.Modifications to the oxide layer may provide or enhance hydrophilicproperties of a surface of the catheter. Hydrophilic properties mayallow surface to bind to water molecules to the exclusion of plasmaproteins. Modifying the oxide layer may increase surface wettability.The surface wettability may have a contact angle measurement of lessthan 20 degrees. The oxide layer may be modified by one of heattreatment, electropolishing, or acid passivation. Modification of theoxide layer may result in an oxide layer having a thickness that is lessthan 5000 picometers, less than 3000 picometers, or less than 2000picometers. Modification of the oxide layer may result in an oxide layerthickness greater than 200 picometers, greater than 400 picometers, orgreater than 600 picometers. The cage and/or the impeller may comprisesa transition metal from period 4, D-block of the periodic table and theoxide comprises an oxide of said period 4 transition metals.

In some embodiments, the cage and/or impeller comprise a surface layerand the surface layer comprises an enriched concentration of titanium orchromium. The surface layer may comprise a metal oxide of titanium oxide(TiO), titanium dioxide (TiO₂), dititanium trioxide (Ti₂O₃), chromium(II) oxide (CrO), chromium (III) oxide (Cr₂O₃), chromium dioxide (CrO₂),chromium trioxide (CrO₃), chromium (IV) or any combination thereof.

In certain embodiments, the hydrophilic surface may be characterized ascomprising a water contact angle of 20 degrees or less, for example, thehydrophilic surface may comprise a water contact angle of 10 degrees orless. In certain embodiments, the modified surface chemistry comprises asuper-hydrophilic surface, for example, with a water contact angle ofless than 10 degrees.

In some embodiments, the modified surface chemistry comprises ahydrophilic functional group. The hydrophilic functional group maycomprise one or more of a hydroxy group, a carboxyl group, an aminegroup, a carbonyl group, a chloro group, an ether group, or a phosphategroup.

In some embodiments, the modified surface chemistry comprises a firstatom and a second atom, the first atom forming a chemical bond with anoxide layer of a surface of the cage and/or impeller and said secondatom forming a bond with said first atom. The first atom comprising afirst electronegativity and the second atom comprising a secondelectronegativity and the difference between said electronegativities isequal to or greater than 0.8, or is equal to or greater 1.0, or is equalto or greater 1.2, or is equal to or greater 1.5.

In some embodiments, the catheter further comprises a cuff. The cuff mayprovide a smooth transition between an outer surface of the catheter anda proximal portion of the cage. The cuff may comprise a modified surfacechemistry, such as a coating or a treatment. In some embodiments, adistal portion of a shaft of the impeller and a distal portion of thecage defines a gap. At least one of the distal portion of the shaft orthe distal portion of the cage defining the gap comprises the modifiedsurface chemistry so as to prevent blood from clotting the gap.

In some aspects, devices of the invention are useful for treating edema.Devices may include a catheter that is dimensioned for insertion into avein, such as a jugular vein. The catheter comprises a proximal portionand a distal portion with a cage attached to the distal portion. Thecage housing an impeller. An expandable member may be attached to anexterior surface of the cage. The expandable member may be, for example,a balloon. Expansion of the expandable member may stabilize the distalportion of the catheter inside the vein and also help to impede anddirect fluid flow into one or more inlets disposed on the cage. Theexpandable member may be shaped so as to direct fluid flow into theinlets without creating disturbances in the flow, thereby reducing shearforces acting on blood particles to further reduce incidences ofthrombosis.

Aspects of the invention provide a method for treating edema. The methodincludes the steps of inserting an indwelling catheter inside apatient's vein wherein the catheter includes a modified surfacechemistry comprising one of a treatment or a coating. Preferably, aportion of a cage or a portion of an impeller of the catheter comprisesthe modified surface chemistry. Preferably, both the cage and theimpeller comprise the modified surface chemistry. The method furtherincludes operating an impeller inside the patient's vein to increase aflow of blood through the vein and create a decrease in pressure near anoutlet of a lymphatic duct causing fluid to drain from the lymph andinto blood circulation. The method includes modulating a flow of bloodthrough the vein while inhibiting blood clot formation on surfaces ofthe catheter on account of the catheter comprising the modified surfacechemistry. Preferably, the modified surface chemistry enhanceshydrophilic properties of the surface of the catheter. In someembodiments, the modified surface chemistry comprises a coating. Thecoating may comprise heparin. In other embodiments, the modified surfacechemistry comprises a treatment that modifies a surface oxide layer.Modification of the oxide layer may provide the catheter with asuper-hydrophilic surface. In some embodiments, the catheter furthercomprises a pressure sensor, the pressure sensor may be designed todetect changes in blood pressure within the vein and adjust a rotationalvelocity of the impeller or a size of an expandable member attached to asurface of the cage accordingly. The device may include a computersystem in communication with the pressure sensor.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an intravascular device.

FIG. 2 shows a partial cutaway view of an impeller assembly.

FIG. 3 shows an inlet of an impeller assembly.

FIG. 4 shows an outlet of an impeller assembly.

FIG. 5 shows a portion of a cage comprising an inlet with anon-thrombogenic surface.

FIG. 6 shows an impeller.

FIG. 7 shows an impeller assembly with an expandable member.

FIG. 8 shows a distal view of an impeller assembly.

FIG. 9 shows an impeller.

FIG. 10 shows an inlet region of a cage with a cuff removed.

FIG. 11 shows an exemplary cage.

FIG. 12 shows a scanning electron microscope image of a surface of aconventional metal cage at high magnification.

FIG. 13 shows plasma proteins and interstices of a surface with a Ra of800 nanometers.

FIG. 14 shows plasma proteins and interstices of a surface with a Ra of50 nanometers.

FIG. 15 shows a metal substrate with a modified surface chemistry.

FIG. 16 shows a portion of the periodic table with electronegativity(EN) values.

FIG. 17 shows a schematic stress strain curve for an elastomer.

FIG. 18 shows an exemplary impeller assembly with an expandable memberin a collapsed state.

FIG. 19 shows an exemplary impeller assembly an expandable member.

FIG. 20 shows an alternative embodiment of an expandable member.

FIG. 21 shows an alternative expandable member balloon of the invention.

FIG. 22 shows a surface roughness characterization of a portion of asurface of a cage.

FIG. 23 shows a surface roughness characterization of a portion of cage.

FIG. 24 shows a standard microscopy image of a surface of a cage.

FIG. 25 shows a portion of the periodic table of elements.

FIG. 26 illustrates a cross sectional view of a portion of a metallicbody comprising a cage or an impeller.

FIG. 27 shows a schematic of a lattice structure of a surface film.

FIG. 28 shows a triol coupling agent.

DETAILED DESCRIPTION

This disclosure relates to devices and methods for treating medicalconditions such as edema or congestive heart failure. The disclosureprovides intravascular devices, e.g., indwelling catheters, capable ofresiding in a patient's bloodstream for prolonged periods of timewithout causing thrombosis. The intravascular devices of the disclosureinclude non-thrombogenic surfaces that improve blood compatibility byreducing device-related thrombus formation and inflammatory reactions.The non-thrombogenic surfaces provided by this disclosure includesurface topographies (e.g., surface roughness) and modified chemistries(e.g., coatings and/or treatments), which prevent thrombosis by reducinglocal shear forces and inhibiting adhesion of blood clotting factors.Moreover, intravascular devices provided by the disclosure includecertain geometric features to efficiently manipulate fluid flow patternsthrough the device with minimal disturbances to further reduce shearforces acting on blood.

Intravascular devices of the invention are designed to inhibit and/orprevent thrombosis on account of optimized fluid flow patterns andsurfaces that inhibit activation of blood defense mechanisms andadherence of certain blood clotting factors. In some aspects, thedisclosure relates to non-thrombogenic materials and surfacemodifications for use in indwelling catheters such as those described inco-owned world application PCT/US2020/019901, which is incorporatedherein by reference.

FIG. 1 shows an intravascular device 101. The device 101 comprises acatheter 103 dimensioned for insertion into a vein, such as, a jugularvein, a subclavian vein, an axillary vein, femoral vein, etc. Thecatheter 103 may be dimensioned for insertion into a vein on account ofits size and shape. The catheter 103 has a proximal portion 107 and adistal portion 109. Preferably the distal portion 109 comprises animpeller assembly 111 comprising a cage 113 with an impeller rotatablydisposed therein. In preferred embodiments, an expandable member 115 isattached to an outer surface of the cage 113. The expandable member 115may comprise a deployed and collapsed configuration and in the deployedconfiguration may help anchor the device inside of the vein and alsofunction to impede, inhibit, or direct blood flow. The collapsedconfiguration may be helpful for delivery and retrieval of the catheter103.

When a distal portion 109 of the intravascular device 101 is insertedinto a vein, such as a jugular vein, the device may be operated so thatthe impeller disposed within the cage 113 rotates. The rotation of theimpeller can create a force which urges fluid (e.g., blood) through thecage 113. In preferred embodiments, the intravascular device 101 may beused to treat edema. The intravascular device may, for example, beinserted into a jugular vein and directed into the vicinity of an outletof a lymphatic duct. The impeller may be operated by, for example,turning on a motor that is operably connected to the impeller via adrive cable disposed within the catheter 103, thereby causing theimpeller to rotate and urging fluid through the cage 113. According toBernoulli's principle, the increase in flow of fluid through the jugularvein may cause a decrease in pressure near the outlet of the lymphaticduct, thereby causing fluid (e.g., lymph) to drain from lymph duct andinto the blood stream.

FIG. 2 shows a partial cutaway view of an impeller assembly 211. Theimpeller assembly 211 includes a cage 213 housing an impeller 217. Inpreferred embodiments, the impeller assembly 211 includes an expandablemember 215 aligned over an outer surface of the cage 213. The cage 213may be attached to a distal portion 209 of the catheter 203. When theimpeller 217 is operated inside a vein, fluid, such as blood, is pulledinto one or more inlets 219 disposed on a proximal portion of the cage213. The fluid then flows through the cage 213 and is propelled out oneor more outlets 221 of a distal portion of the cage 213. Preferably, theimpeller assembly 211 is shaped such that as fluid flows through thecage 213 via the inlets 219 and outlets 221, the fluid exhibits a smoothlaminar flow without disturbances such as recirculation or vortices. Asmooth laminar flow is advantageous as it may reduce shear forces actingon particles within the fluid, e.g., blood cells, which may otherwisecause unwanted affects, e.g., blood clots.

In some aspects, the invention provides a thrombosis-resistantintravascular device, such as an indwelling catheter 203. The catheter203 may include an impeller assembly 211 with a cage 213 housing animpeller 217 connected to a distal portion 209 of the catheter 203. Atleast a portion of a surface 225 of the cage 213 and/or the impeller 217comprises a non-thrombogenic surface texture, i.e., surface roughness.

Thrombogenicity refers to the tendency of a material in contact with theblood to produce a thrombus, or clot. It not only refers to fixedthrombi but also to emboli, thrombi which have become detached andtravel through the bloodstream. Thrombogenicity may include events suchas the activation of immune pathways and the complement system. Ingeneral, all materials are considered to be thrombogenic to a degreewith the exception of endothelial cells which line blood vessels. Asused herein, non-thrombogenic materials or surfaces refer to materialsor surfaces with properties which reduce thrombogenicity. As such, thenon-thrombogenic materials or surfaces described herein refer tomaterials and surfaces comprising features that reduce incidences ofthrombosis.

Thrombus formation may be the result of at least two interdependentmechanisms, platelets and circulating protein clotting factors.Platelets, small anuclear cells that circulate in blood in ranges from150×106/mL to 400×106/mL are one component of hemostasis. Activation ofplatelets by a variety of stimuli initiate complex pathways that resultin platelet aggregation and the release of potent pro-thromboticmolecules. Blood contact with artificial surfaces may elicit plateletactivation by a variety of mechanisms, including device relatedalteration in blood flow that trigger shear-related platelet activation,and due to direct platelet adherence to the deposited protein layer onsynthetic surfaces of the device. Activated platelets undergo dramaticshape changes which promote aggregation with other platelets, andrelease platelet and pro-coagulant agonists (such as thromboxane A2,ADP, and FVa). The phospholipids of the platelet membrane also serve asthe substrate for activated clotting factors, resulting in localamplification of the coagulation cascade. Aggregation of platelets,together with explosive activation of protein clotting factors, mayresult in significant thrombus accumulation on the device surface,embolization of thrombus particles into the bloodstream, and may causedetectable reductions in circulating platelet count (consumption ofplatelets).

Roughness plays an important role in determining how an object willinteract with its environment, and in the context of the presentdisclosure, plays an important role in determining how blood willinteract with the intravascular device by influencing whether bloodclots are likely to form. A smooth surface is less likely to initiate ablood defense mechanism such as causing the formation of a blood clotthan a rough surface.

The non-thrombogenic surface texture may be characterized by itsarithmetic average roughness (Ra), which is the arithmetic average ofabsolute values of roughness profile ordinates. In particular, Ra is thearithmetic average of the absolute values of the measured profile heightdeviations taken within the sampling length and measured from thegraphical center line. Surface roughness, as measured by Ra, is acomponent of surface texture and may be quantified by the deviations inthe direction of the normal vector of a real surface from its idealform. If the deviations are large, the surface is rough; if they aresmall, the surface is smooth. Preferably, the deviations are small. Rais generally expressed in micrometers. Although, as used herein, Ravalues shall are expressed in nanometers. In some aspects, thedisclosure provides an indwelling device, e.g., a catheter, comprising asurface texture with a Ra of less than 75 nanometers.

Surface roughness measurements, such as Ra, may be measured using atomicforce microscopy (AFM), for example, as described in Webb, 2012,Roughness Parameters for Standard Description of Surface,Nanoarchitecture, Scanning: Vol. 34, 257-263, incorporated by reference.Alternatively, surface roughness may be measured using a surfaceroughness tester such as the surface roughness tester sold under thetrade name Phase II, SGR-4600, Surface Roughness Tester/Profilometer byPhase II (Upper Saddle River, N.J.).

In preferred embodiments, at least a portion of a surface of the cage213 or the impeller 217 comprises a non-thrombogenic surface texturewith a Ra value of less than 50 nanometers. Preferably, the Ra value isless than 25 nanometers. In some embodiments, at least a portion of thecage 213 comprises the non-thrombogenic surface texture. The portion ofthe cage 213 comprising the non-thrombogenic surface texture may besubstantially all of exposed portions of the cage 213 that contactsblood when the device is operating inside a vein. In other embodiments,only portions of the cage 213 that comprise the inlets 219 and/oroutlets 221 may have the non-thrombogenic surface texture as these areasmay be more prone to blood protein adhesion or blood particle shearingdue to certain patterns of fluid flow. In some embodiments, at least aportion of the impeller 217 comprises the non-thrombogenic surfacetexture with a Ra value of less than 50 nanometers. For example, theportion of the impeller 217 that contacts blood while the impeller 217is operating inside the vein may comprise the non-thrombogenic surfacetexture to prevent blood proteins from sticking to the impeller andcreating blood clots. In preferred embodiments, portions of both thecage 213 and the impeller 217 comprise a non-thrombogenic surfacetexture with, for example, a Ra value of less than 50 nanometers.

Catheters 203 of the invention are particularly well suited forintravascular treatments on account of their non-thrombogenicproperties. In certain aspects, catheters 203 of the invention includenon-thrombogenic surface textures having a Ra value of less than 50nanometers. The non-thrombogenic surface texture inhibits and/orprevents thrombosis by inhibiting the adherence of platelets and bloodproteins onto surfaces of the catheter 203 when the catheter 203 isinserted into a patient's vein. In other aspects, the non-thrombogenicsurface texture inhibits and/or prevents thrombosis by reducing shearforces acting on blood particles flowing through the catheter 203 sincea smooth surface is less likely to shear a particle, such as a bloodcell, than a rough surface.

The non-thrombogenic surface texture of devices of this disclosure maybe formed by processing a metal. Processing a metal may include one ormore of sanding, tumbling, polishing, electropolishing, grinding,lapping, or abrasive blasting, for example, see, Chapter 82—MetalProcessing and Metal Working Industry, Encyclopedia of OccupationalHealth and Safety 4th Edition, which is incorporated by reference.Preferably, the metal is processed by electropolishing, for example, asdescribed in Cutchin, 2015, Electropolishing applications andtechniques, The Tube & Pipe Journal, incorporated by reference. Forexample, a surface texture with a Ra of less than 50 nanometers may begenerated by obtaining a piece of metal and rubbing abrasive particlesagainst the surface of the metal to create a random, non-linear surfacetexture with a Ra of less than 50 nanometers. Different abrasive mediamay be used. A size of the cutting grains is generally referred to as“grit”, and the higher the grit number, the smaller and finer theparticles are and hence the finer the surface finish they are able toachieve. Preferably, a higher grit number is used to achieve a smoothsurface.

Because devices of the invention are more efficient than other devicesand pump blood without initiating thrombosis, devices of the inventionare beneficial for treating patients with edema. As such, in someaspects, the invention provides a method for treating edema. The methodmay include inserting into an innominate vein of a patient a distalportion 209 of a catheter 203 comprising an impeller assembly 211 with acage 213 and an impeller 217 therein. A portion of at least one of thecage 213 or the impeller 217 comprises a non-thrombogenic surfacetexture with a Ra value of less than 50 nanometers. Preferably, both thecage 213 and the impeller 217 comprise the non-thrombogenic surfacetexture. For example, in preferred embodiments, substantially allportions of the cage 213 and the impeller 217 that are exposed to bloodwhen the distal portion 209 of the catheter 203 is inserted into thevein will comprise the non-thrombogenic surface texture. For thetreatment of edema, the method includes activating the impeller 217with, for example, a motor connected to a proximal portion of thecatheter 203. Activation of the impeller 217 increases fluid flowthrough the innominate vein, thereby decreasing pressure at a lymphaticduct. A proximal portion of the cage 213 may be shaped to facilitateflow into an inlet 219 without recirculation or adherence of bloodproteins to surfaces of the cage 213. Additionally, as discussed herein,the catheter 203 may include other features (e.g., coatings, materials,designs) that prevent or inhibit thrombosis by inhibiting adherence ofblood clotting factors to surfaces of the catheter 203 or reducing shearforces. In some embodiments, methods of the invention further includethe step of preparing a catheter 203 for treating edema by, for example,processing a metal. The metal may comprise one of the cage 213 or theimpeller 217. Processing may involve one of sanding, tumbling,polishing, electropolishing, grinding, lapping, or abrasive blasting,the metal such that a portion of a surface of one or both of the cage213 and the impeller 217 have a surface Ra of less than 50 nanometers,for example, 25 nanometers.

The non-thrombogenic surface texture may comprise an average depth ofroughness (Rz) of less than 175 nanometers. Rz is the average distancebetween the highest peak and the deepest valley in five samplinglengths, or cutoffs across a surface. Rz may be calculated by measuringvertical distance from the highest peak to the lowest valley within fivesampling lengths, then averaging these distances.

In some embodiments, the invention provides a catheter 203 with animpeller assembly 217 disposed at a distal portion 209. The impellerassembly 217 comprising a cage 213 housing an impeller 217 wherein atleast a portion of a surface of the cage 213 or the impeller 217comprises a non-thrombogenic surface texture having a Rz value of lessthan 175 nm. Preferably, the Rz value of the non-thrombogenic surface isless than 175 nanometers. For example, the Rz value may be less than 100nanometers.

In preferred embodiments, the impeller assembly 211 includes anexpandable member 215 attached to an exterior surface of the cage 213.The expandable member 215 may be expanded to apply a radial outwardforce to a blood vessel wall. The device may be shaped such thatapplication of the outward radial force substantially fixes at least aportion of the impeller assembly 217 to a central axis of the vesselwall. Upon expansion of the expandable member 215, the expandable member215 may occludes the vein and directs blood flow into an inlet 219 ofthe cage. Preferably, the expandable member is a balloon. When theexpandable member 215 is inflated, a proximal portion of the expandablemember 215 may help to facilitate flow into an inlet 219 of the cage 213by funneling blood therein. Additionally, when the expandable member 215is inflated, a distal portion of the expandable member 215 may bealigned over outlets of the cage to mitigate blood recirculation. Asdiscussed herein, the impeller assembly 217 may include features thatfacilitate blood flow through the cage 213.

In other aspects, the invention provides intravascular devices on whicha surface of the device has been chemically modified to prevent theactivation of blood defense mechanisms. The device comprises a catheter203 dimensioned for insertion into a vein such as a jugular vein. Thecatheter 203 includes a proximal portion and a distal portion 209. Animpeller assembly 217 may be attached to the distal portion 209 of thecatheter 203, the impeller assembly 217 comprising a cage 213 with animpeller 217 rotatably disposed therein. The impeller assembly 211 maybe designed to inhibit thrombosis on account of at least a portion ofthe cage 213 and/or the impeller 217 comprising a modified surfacechemistry provided by at least one of a coating or a surface treatment.A modified surface chemistry may include a surface having a physical,chemical, or biological characteristic that different from what is foundon the surface of a conventional intravascular device.

Modified surface chemistries of this disclosure may comprise a coatingor a treatment. The modified surface chemistry may be a coatingcomprising a blood anticoagulant. For example, the coating may comprisea heparin coating such as those described in Biran, 2017, Heparincoatings for improving blood compatibility of medical devices, Adv DrugDelivery Rev 112:12-23, incorporated by reference. Heparin binds toantithrombin. Antithrombin is a serine protease inhibitor and inhibitorof blood clotting factors. Thus, in some embodiments, catheters of thedisclosure display anti-thrombogenic properties on account of coatingswith surfaces having an affinity for antithrombin. In some embodiments,heparin may be immobilized on a surface of the cage 213 or the impeller217 by attaching heparin to a compatible functional group deposited onthe surface of the cage 213 or the impeller 217 or by priming thesurface of the cage 213 or the impeller 217 with a matrix onto whichheparin may covalently bind. As an example, the coating may includepre-assembled aggregates of heparin molecules such as found in thecoating sold under the trade name CHC, by Corline Biomedical AB, Sweden.In some embodiments, the coating may comprise heparin that is covalentlybonded to a hydrophilic priming layer such as found in the heparincoating sold under the trade name ASTUTE by Biointeractions Ltd.Alternatively, heparin devices of the disclosure may include arelease-based approach, wherein small amounts of heparin are releasedovertime. Alternatively, the coating may comprise warfarin, which is ananticoagulant used to reduce the formation of blood clots.

In some embodiments, the modified surface chemistry may comprise ahydrophilic coating that establishes or enhances hydrophilic propertiesof a surface of the catheter 203. Hydrophilic surfaces attract water andallow wetting of the surface. Hydrophilic surfaces generally have adroplet contact angle measurement of less than 90 degrees. Providinghydrophilic surfaces on portions of the catheter 203 such as at leastone of the cage 213 and/or the impeller 217 is advantageous forpreventing thrombosis because hydrophilic surfaces may adhere to watermolecules present in blood to the exclusion of blood clotting factors.In some instances, upon inserting the catheter inside the vein, thehydrophilic surface of the cage 213 and/or the impeller 217 may create alayer of water molecules on the hydrophilic surface that functions as abarrier preventing plasma protein adherence by eliminating possiblebinding sites.

The hydrophilic coating may be made by treating a surface of thecatheter 203 with an acid, such as hyaluronic acid, for example, asprovided by the hydrophilic coating sold under the trade name Hydak, byBiocoat, Inc., Horsham, Pa. In other embodiments, the coating may bemade by, for example, submerging a portion of the catheter 203 in awetting fluid. The wetting fluid may comprise a salt of an organic acid,for example, a benzoate or a sorbate, and a pH buffer. In otherembodiments, the coating may comprise a hydrophilic coating such as thecoating sold under the trade name Acuwet by Aculon, San Diego, Calif.

In some embodiments, the modified surface chemistry comprises a modifiedoxide layer. Oxide layers are layers formed by the reaction of amaterial's surface with oxygen. Modifications to the oxide layer includechanges in thickness, topography, and chemical composition. Suchmodifications are useful for improving surface wettability which reducesadherence of blood clotting factors. In some instances, the oxide layeris formed or modified by one of electropolishing, heat treatment, oracid passivation. Preferably, the oxide layer is modified byelectropolishing, also known as electrochemical polishing, anodicpolishing, or electrolytic polishing (especially in the metallographyfield). Electropolishing is an electrochemical process that removesmaterial from a metallic workpiece and may also be used to reducesurface roughness by levelling micro-peaks and valleys, therebyimproving the surface finish. Methods of modifying the oxide layer mayremove or reduce organic contaminants present on the surface of thecatheter, which may further improve hydrophilicity. In preferredembodiments, the modified surface chemistry may be provided by a surfaceoxidation.

The modified surface chemistry may be generated by a surface oxidetreatment that includes plasma electrolytic oxidation, also known aselectrolytic plasma oxidation or microarc oxidation. Plasma electrolyticoxidation comprises an electrochemical surface treatment process forgenerating oxide coatings on metals. Plasma electrolytic oxidationincludes high potentials that create discharges resulting in plasma thatmodifies the structure of the oxide layer. This process can be used toproduce oxide coatings on metals.

In some embodiments, the modified surface may further comprises one of ametal oxide of titanium oxide (TiO), titanium dioxide (TiO₂), dititaniumtrioxide (Ti₂O₃), chromium (II) oxide (CrO), chromium (III) oxide(Cr₂O₃), chromium dioxide (CrO₂), chromium trioxide (CrO₃), chromium(IV) or any combination thereof. In some embodiments, at least one ofthe cage 213 or the impeller 217 comprises a modification to the oxidelayer and the thickness of the oxide layer provides improvedbiocompatibility of the device. The thickness of the oxide layer may be,for example, less than 5000 picometers, less than 3000 picometers, lessthan 2000 picometers, or is greater than 200 picometers, greater than400 picometers, or greater than 600 picometers. In some embodiments, amodification to the oxide layer comprises replacing a portion of thesurface's native oxide layer with a more uniform oxide layer.

Aspects of the invention provide an indwelling catheter in which atleast a portion of the cage 213 or the impeller 217 comprises a modifiedsurface chemistry (e.g., a treatment or coating). In some embodiments,substantially all of a surface of the cage 213 that is exposed to bloodwhen the cage 213 is positioned inside of a vein will comprise themodified surface chemistry. Substantially all generally means greaterthan at least 50 percent, for example, at least 75 percent of a portionof the cage 113 that is exposed to blood inside the vein. In someembodiments, portions of the cage 113 comprising inlets 219 and outlets221 will comprise the modified surface chemistry as these portions maybe particularly prone to thrombosis due to fluid flow patterns that mayexist such as recirculation. In some embodiments, inner surfaces of thecage 113 that contact blood will comprise the modified surfacechemistry.

In some embodiments, portions of the impeller 217 may comprise themodified surface chemistry. For example, greater than at least 50percent of the impeller 217 that is exposed to blood when the catheter203 is inside the vein may comprise the modified surface chemistry.Preferably, both of the cage 213 and the impeller 217 comprise themodified surface chemistry in order provide the greatest protectionagainst thrombosis.

In some embodiments, one or more portions of at least one of the cage213 and/or the impeller 217 comprises a surface texture having a Ravalue of less than 50 nanometers in addition to a modified surfacechemistry. Preferably, portions comprising the surface texture and themodified surface chemistry overlap such that some areas of the cage 213and/or the impeller 217 include both a surface texture having an Rzvalue of less than 150 nanometers and a modified surface chemistry suchas a coating or treatment that may increase hydrophilicity. The modifiedsurface chemistry may follow the contours and roughness of the cage 213or the impeller 217. In some embodiments, the modified surface chemistrycomprises a coating thickness and the coating thickness is greater thanthe Rz of the surface of the cage 213 or the impeller 217.

In preferred embodiments, the modified surface chemistry is provided onportions of the cage 213 and/or the impeller 217 and provides ahydrophilic surface comprising a water contact angle of 20 degrees orless, for example, the surface may comprise a water contact angle of 10degrees or less. The water contact angle is the angle that a droplet ofwater creates with a solid (e.g., the cage 213 or impeller 21) when thewater droplet is deposited on the solid. In some embodiments, themodified surface chemistry comprises a super-hydrophilic surface. Asuper-hydrophilic comprises a static contact angle of less than 10degrees and may have a rolling-off angle of greater than 10 degrees. Theroll-off angle is the angle of inclination of a surface at which a droprolls off. The super-hydrophilic surface may be generated by modifyingan oxide layer of the surface of the cage 213 or the impeller 217.

In some embodiments, the modified surface chemistry comprises ahydrophilic functional group. Functional groups are groups of chemicalsthat are attached to carbon atoms in the place of hydrogen atoms andhydrophilic functional groups are functional groups that are “waterloving”, i.e., hydrophilic in nature. For example, the hydrophilicfunctional group may comprise one or more of a hydroxy group, a carboxylgroup, an amine group, a carbonyl group, a chloro group, an ether group,or a phosphate group.

The modified surface chemistry may comprise a coating. Preferably, thecoating comprises at least one of a polysaccharide, a polymer, or ahydrogel. The coating may further comprise one or more of apolyurethane, polyethylene glycol, poly-2-oxazolines, polyvinyl alcohol,polyvinylpyrrolidone, maleic anhydride copolymer,poly(lactide-co-glycolide), aminoalkyl(meth)acrylamide,aminopropylmethacrylamide, copolymers and blends of the aforementioned.In some instances, the coating further comprises one ofpolyethyleneimine, polyurethane, a sulfonate group, albumin, apolyamine, polyvinyl siloxane, hyaluronic acid, or any combinationthereof.

In some embodiments, the modified surface chemistry may comprise acoating comprising a polysaccharide. Preferably, the polysaccharidecomprises heparin. Heparin, also known as unfractionated heparin, is amedication and naturally occurring glycosaminoglycan. Heparin decreasesthe clotting ability of the blood. Coating a surface of the catheter,such as a portion of at least one of the cage 213 or the impeller 217,may reduce risks of blood clots as well as catheter-related blood streaminfections and bacterial colonization of the catheter 203.

Devices of the invention may minimize risks of thrombosis formation byincorporating non-thrombogenic materials. As used herein, anon-thrombogenic material is a material having minimal thrombogenicaffects when inserted into a blood stream. According to some aspects ofthe disclosure, intravascular devices are provided comprising a catheter203 dimensioned for inserting into a vein, such as a jugular vein. Thecatheter 203 comprising a proximal portion and a distal portion 209; anda cage 213 attached to the distal portion 209 of the catheter 203, thecage 213 housing an impeller 217, wherein a portion of a surface of thecage or the impeller comprises a non-thrombogenic metal. In someembodiments, the non-thrombogenic metal is, for example, titanium.Preferably, the non-thrombogenic metal includes an oxide layermodification that renders the surface highly hydrophilic. Preferably,the modification improves uniformity of the oxide layer. The oxide layermay be modified by a treatment. For example, the treatment may compriseone of electropolishing, heat treatment, or acid passivation. Thetreatment may comprise a surface oxidation treatment that removes andgenerates new oxide layers.

Preferably, at least one of the cage 213 or the impeller 217 comprisesthe non-thrombogenic metal. In some embodiments, the cage 213 comprisesthe non-thrombogenic metal. For example, in some embodiments,substantially the entire surface of the cage 213 or the impeller 217that is in contact with blood when the catheter is inside the vein hasthe non-thrombogenic metal.

The non-thrombogenic metal may comprise a transition metal or apost-transition metal. Transitional metals are any of the set ofmetallic elements occupying a central block (i.e, groups IVB-VIII, IB,and BB, or 4-12) in the periodic table, e.g., iron, manganese, chromium,and copper. Post transition metals, also known as the poor metals, are agroup of metals on the periodic table, positioned the right of thetransition metals. The group 12 elements may be included. Germanium,antimony, and polonium also may be included. Preferably, thenon-thrombogenic metal comprises one of titanium, cobalt, nickel,zirconium, gold, silver, or iridium, aluminum, tin, gallium, stainlesssteel, or nickel titanium. The non-thrombogenic metal may be selected onaccount of its hydrophilic properties that inhibit blood clots while thecatheter is inside the vein.

In preferred embodiments, devices of the invention includenon-thrombogenic metals comprising one or more of a non-thrombogenicsurface texture and/or non-thrombogenic modified surface chemistry asdescribed herein. In some embodiments, the cage 213 and/or impeller 217comprise a surface layer and the surface layer comprises an enrichedconcentration of titanium or chromium.

In some aspects, the invention provides an intravascular device usefulfor treating medical conditions such as edema. The device comprises acatheter 2003 dimensioned for insertion into a vein. The catheter 203comprises a proximal portion and a distal portion 209; a cage 213attached to the distal portion of the catheter 203; and an expandablemember 215 attached to an exterior surface of the cage 213, wherein aportion of a surface of the expandable member 215 is non-thrombogenic,i.e., comprises properties that reduce thrombosis.

In some embodiments the non-thrombogenic surface of the expandablemember 215 comprises a block copolymer comprising a first polymericblock and a second polymeric block. A block copolymer is a copolymerformed when, for example, two monomers cluster together and form‘blocks’ of repeating units. For example, a polymer made up of X and Ymonomers joined together like: -Y-Y-Y-Y-Y-X-X-X-X-X-Y-Y-Y-Y-Y-X-X-X-X-X-is a block copolymer where -Y-Y-Y-Y-Y- and -X-X-X-X-X- groups are theblocks. In some preferred embodiments, a polymeric block comprises ahydrophilic functional group. Hydrophilic functional groups may includeether groups, amine groups, urethane groups, urea groups, ester groups,hydroxyl groups, carbonyl groups, carboxyl groups, amino groups,sulfhydryl groups, or phosphate groups. In another preferred embodimentthe polymeric block comprises functional groups that confer rigidity tothe block. Functional groups conferring rigidity may be aromatic oraliphatic. Functional groups conferring rigidity may include groups thatcomprise a ring structure. These ring structured groups may be aromaticor aliphatic. The hard block may comprise a mix of ring structure groupsand linear groups. Linear groups may include amine groups, urethanegroups, urea groups, carbonate groups and methylene groups. A secondpolymeric block may comprise a polymer repeat unit selected to enhanceflexibility in the second polymeric block. The second block may comprisea polyether, a polyester, a polycarbonate, a polybutadiene, apolydimethylsiloxane or a mixture of these. The first and secondpolymeric blocks may be substantially immiscible and when copolymerizedform phase separated blocks within a polymer matrix. The phaseseparation may be manifested on a surface of said expandable member 215.In some instances, the polymer may comprise non-bound chemical species,the non-bound chemical species comprising oligomers and additives. Thepolymer may be treated so as to remove non-bound chemicals and furthermanifest the phase separation on the surface of the expandable member215. Moreover, by removing the non-bound chemicals, hydrophilicity ofthe surface may be improved.

The non-thrombogenic surface of the expandable member 215 may comprisesa hydrophilic coating and/or a hydrophilic material. When inside a vein,the hydrophilic coating or hydrophilic material of the expandable member215 may bind to water molecules to the exclusion of blood plasmaproteins, thereby preventing blood clots. In some embodiments, thesurface of the expandable member 215 includes one or more portions withthe hydrophilic coating and portions without the hydrophilic coating.The one or more portions with and without the hydrophilic coating mayform a pattern, the pattern may be more apparent when the expandablemember 215 is in an expanded state. The pattern may increase thenon-thrombogenic properties of the surface of the expandable member 215and further help to reduce blood clotting. The pattern may, for example,improve non-thrombogenic properties of the device by disrupting bloodclotting factors from adhering to portions of the catheter including theexpandable member 215. For example, the pattern may comprise stripes,spirals, waves, or may be a zebra pattern.

The hydrophilic coating may comprise one of a polysaccharide, a polymer,or a hydrogel. Polysaccharides are long chains of carbohydratemolecules, specifically polymeric carbohydrates composed ofmonosaccharide units bound together by glycosidic linkages. In preferredembodiments, the polysaccharide comprises heparin. In some embodiments,the expandable member 215 comprises a polymer, the polymer comprisingsilicon.

Aspects of the invention provide a catheter 203 comprising an expandablemember 215. The expandable member 215 includes features such asmaterials and coatings that inhibit thrombosis. Preferably, theexpandable member 215 comprises hydrophilic materials. For example, thematerial may comprise one of polyethylene terephthalate, polyamide,polyurethane, or nylon. Preferably, the expandable member 215 comprisespolyurethane. In some embodiments, the expandable member 215 furtherincludes a hydrophilic coating. The hydrophilic coating may comprisesmore than half of the surface of the expandable member 215 that isexposed to blood when the expandable member is in an expanded stateinside the vein. In some embodiments, the expandable member 215comprises a hydrophilic coating on a proximal portion and/or a distalportion, which may align with inlets 219 and outlets 221 of the catheter203 when the expandable member 215 is in a deployed state.

Preferably, the expandable member is a balloon, and upon expansion ofthe balloon inside a vein, the balloon opposes a wall of the vein andhelps direct blood flow into an inlet 219 of the cage 213. Moreover,upon expansion of the balloon, a distal-most portion of the balloon maybe aligned over the inlets 219 or the outlets 221 to mitigate bloodrecirculation. Mitigation of blood recirculation may further reducethrombogenicity of the device by minimizing shear forces acting on bloodparticles.

FIG. 3 shows an inlet 319 of an impeller assembly. The inlet 319 isdefined by a plurality of struts 331. One or more of the struts 331 maycomprise an inflation lumen (not shown) that connects to an expandablemember and may be used to, for example, deliver fluid to the expandablemember for inflation.

FIG. 4 shows an outlet 421 of an impeller assembly. The outlet 421 is atleast partially defined by a plurality of struts 431 and at leastpartially aligns with an impeller 417 disposed within the impellerassembly. An angle of the impeller 417 extends upwards towards aproximal portion of the impeller assembly. The upward angle of theimpeller 417 provides a surface that guides a flow of fluid exiting theimpeller assembly. In particular, the surface is optimized so as tofacilitate the flow of fluid from the impeller assembly such that thefluid experiences minimal to no disturbances in flow such as vortices.

FIG. 5 shows a portion of a cage 513 comprising an inlet 519 with anon-thrombogenic surface finish. In particular, the cage 513 comprises ametal and portions of the metal have been processed by, for example,electropolishing such that the cage 513 has non-thrombogenic surfacefinishes. Portions of the cage 513 having the non-thrombogenic surfacefinish include the inlets 519. The cage 513 further includes a roughsurface 533 formed by, for example, etching. The rough surface may beprovided for an improved interfacial adhesion between an expandablemember and the cage 513.

FIG. 6 shows an impeller 617. As described herein, the impeller 617 maybe disposed within an impeller assembly and connected to a motor by aflexible drive cable 637 that extends through the catheter connectingthe motor to the impeller. The drive cable 637 may comprise a metal suchas nickel-titanium alloy, i.e., nitinol, selected for itsbiocompatibility, kink resistance, and elasticity properties. The drivecable 637 may comprise a non-thrombogenic surface texture having a Ravalue of 75 nanometers or less, preferably 50 nanometers. In someinstances, the drive cable 637 comprises a polyether ether ketone (PEEK)liner for providing biocompatibility and reduced friction. The impeller617 comprises at least one blade 639. The impeller blade 639 isconfigured to be in fluidic engagement with the impeller assembly (referto FIG. 2) such that the impeller 617 may rotate in clearance with aninner lumen of the impeller assembly 211 during operation. Bladeclearance may be, for example, between 7-110 micrometers. A radialdimension of the impeller blade 617 may vary across a proximal portionand distal portion of the impeller 617.

FIG. 7 shows an impeller assembly 711 with an expandable member 715. Theexpandable member 715 is shown in an inflated configuration. Preferably,the expandable member comprises a balloon. For example, in preferredembodiments, the expandable member 715 comprises a polyurethane balloon.As discussed herein, the balloon 715 may comprise a coating thatprovides hydrophilic properties. At is distal end of the impellerassembly 711 is an atraumatic tip 741. The atraumatic tip 741 preferablycomprises a soft material such as a polymer. The material may include,for example, a polyether block amide, such as those sold under thetrademark PEBAX by Arkema Inc. (King of Prussia, Pa.).

FIG. 8 shows a distal view of an impeller assembly 817. The impellerassembly 817 includes an expandable member which is shown in atransparent form. An inflation lumen 843 extends along an outer surfaceof the impeller assembly 817 for inflating the expandable member. Theinflation lumen 843 may, for example, be used to deliver a fluid to theexpandable member thereby causing the expandable member to inflate. Abiologically inert fluid such as saline may be used to inflate theexpandable member by way of the lumen since saline does not react withthe body and is relatively safe in the event that one of the lumen orthe expandable member leaks during operation.

FIG. 9 shows an impeller 917. The impeller may include an optimizedblade impact angle 918 to reduce negative axial velocity (recirculation)of fluid traveling through the cage in which the impeller is housed. Forexample, the optimized blade impact angle may comprise an inclined ortapered surface disposed at a proximal end of the impeller blade 939. Aproximal end of the impeller 917 may be spaced apart from a distal endof a cuff 947. The proximal end of the impeller 917 and the distal endof the cuff 947 may define a gap (not shown). In preferred embodiments,the gap comprises one of a non-thrombogenic surface texture or coating,as discussed above, in order to prevent blood particles such as proteinsand platelets from adhering to gap surfaces and creating clots.

FIG. 10 shows an inlet region 1019 of a cage 1013 with a cuff removed.The cage 1013 comprises reservoirs 1049, for example, 5-6 small holesaround a proximal part of the cage 1013. During manufacturing, thereservoirs 1049 may be filled with an adhesive to bond the cage 1013 tothe cuff on the proximal side. The adhesive seals up the reservoirs andprovides a smooth and biocompatible surface finish. Exemplary adhesivesinclude low viscosity cyanoacrylates and ultraviolet cure adhesives. Asimilar approach may be employed to bond the cage 1013 to a bearinghousing, or catheter tip, on the distal side, as discussed below.

In some embodiments, catheters of the invention further include one ormore sensors that are in operable communication with an expandablemember attached to an outer surface of a cage of an impeller assembly.The one or more sensors may be disposed on the catheter, for example, onthe impeller assembly near an inlet and/or an outlet. The sensors, forexample, pressure sensors, may be used sense a pressure change in a veinin which the catheter is inserted. The pressures sensors may beconfigured to detect changes in pressure and based on detected changesin pressure, may provide data that is used to regulate a flow of fluidthrough the impeller assembly by adjusting a rotational velocity of animpeller disposed therein, the sensors may provide data that is used toadjust a size or shape of the expandable member by, for example, sendingdata to a computer that processes the data and sends instructions to anautomated syringe pump to inflate the expandable member with a fluidsuch as saline.

With reference to FIG. 2, in preferred embodiments, the catheter 203further comprises a cuff 249 attached to a proximal portion of the cage213, the cuff 249 provides a smooth transition between an outer surfaceof the catheter 203 and a proximal portion of the cage 213. In someinstances, the cuff 249 may comprise a non-thrombogenic surface texturehaving, for example, an Ra value of 50 nanometers or less, such as 25nanometers. Alternatively, or in addition to, the cuff 249 may comprisea modified surface chemistry, as discussed above, with, for example, acoating or treatment that enhances hydrophilic properties of a surfaceto preferentially adhere water molecules to the exclusion of bloodproteins. Moreover, the cuff 249 may also comprise a non-thrombogenicmaterial, such as, for example, titanium, and may comprise a surfaceoxidation treatment that removes and generates a new surface oxidelayer.

In some embodiments, a bearing assembly 251 is disposed at a distalportion of the impeller assembly 211. The bearing assembly 251comprising a housing 253 with one or more bearings 257 disposed therein.Preferably, the housing 253 comprises titanium. The bearings 257 may be,for example, ceramic bearings. The bearings 257 provide importantbenefits to the catheter 203 by reducing friction generated by therotational movement of the impeller 217 during operation. The bearings257 may allow the impeller 217 to rotate more freely. The bearinghousing 253 may comprise PEEK, or a metal such as titanium, and mayfurther comprise a non-thrombogenic surface texture or modified surfacechemistry such as a coating and/or treatment, as described herein, toprevent thrombosis while inside a blood vein. In some embodiments, adistal gap 263 is defined by a portion of the bearing assembly 251, orcatheter tip, and the impeller 217. The distal gap 263 may be, forexample, greater than 20 micrometers and less than 60 micrometers. Thedistal gap 263 may be configured so as to allow the impeller 217 torotate efficiently without trapping blood proteins therein. To that end,the distal gap 263 may comprise a non-thrombogenic surface texture ormodified surface chemistry such as a coating and/or treatment, asdescribed herein. For example, surfaces of the impeller 217 and/orbearing assembly 251 which define the distal gap 263 may comprise asurface texture having a RA value of less than 50 nanometers or maycomprise a treatment that modifies an oxide layer of the surface asdiscussed herein.

A proximal gap 265 may be located at the proximal portion of theimpeller assembly 211. The proximal gap 265 may be defined by a portionof the cage 213 and a proximal portion of the impeller 217. The proximalgap 265 may be designed so as to allow the impeller 217 to rotateefficiently without trapping blood proteins therein. To that end, theproximal gap 265 may comprise a non-thrombogenic surface texture ormodified surface chemistry such as a coating and/or treatment, asdescribed herein. For example, surfaces of the impeller 217 and/or cage213 which define the proximal gap 265 may comprise a surface texturehaving a RA value of less than 50 nanometers or may comprise a surfaceoxidation treatment.

Preferably, the cage 213 is substantially cylindrical in shape. The cage213 may be configured to facilitate a flow of fluid through an interiorlumen 261 such that the flow experiences minimal disturbances in flowpatterns such as vortices and recirculation. In particular, the cage 213may be designed so as to include stepped portions that define changes ininner diameters within the cage 213 and manipulate the flow of fluidtherein. In some embodiments, for example, as shown in FIG. 2, the lumen261 of the cage 213 is narrower at a proximal portion than at a distalportion to increase flow rate of fluid traveling through the cage 213.In other embodiments, the lumen 261 of the cage 213 may taper towards,for example, the distal end. In some embodiments, the cage 213 comprisesan outer wall that is thicker at a proximal portion than at a distalportion of the cage 213.

This disclosure provides a catheter comprising a cage. Preferably thecage houses an impeller and at least part of the cage or the impellerhas a thrombogenic resistant surface texture. The surface texture of thecage or impeller may be resistant to thrombosis formation on account ofits smooth surface. In particular, any surface interstices (e.g.,crevices, gaps, spaces) present on the cage or the impeller are madesmaller than potentially adherent plasma proteins thus establishing asurface environment on which the plasma proteins struggle to grip thesurface.

FIG. 11 shows an exemplary cage 1113. The cage 1113 is designed to beattached to a distal portion of a catheter and may be dimensioned forinsertion into a vein or an artery. Preferably, the cage 1113 houses animpeller for facilitating a flow of blood through the cage 1113 whenoperating inside the vein or artery.

FIG. 12 shows a scanning electron microscope image of a surface of aconventional metal cage at high magnification. An inclusion 1251 ormaterial defect is shown on the surface. Depending on a size or profileof the inclusion 1251, the inclusion 1251 may impart a local roughnessthat promotes thrombus formation. The roughness may promote thrombusformation by presenting a gripable surface onto which a blood clottingprotein, e.g., fibrinogen, may adhere.

One insight of the invention is that surface roughness may bemanipulated so as to influence the types of particles, such as plasmaproteins, that may or may not be adsorbed onto the surface. Suchmanipulations may be useful for inhibiting thrombosis formation. Forexample, if the surface roughness, as measured by Ra, is small relativeto a particular plasma protein, e.g., fibrinogen, then that plasmaprotein is less likely to be adsorbed onto the surface. However, smaller(and in some instances more abundant) plasma proteins, e.g., albumin,may be adsorbed if the smaller plasma protein is smaller than anyinterstices provided by the roughness profile. Albumin adsorption is notassociated with a harmful thrombosis response. By modulating the Ra ofthe surface, a surface may be designed to preferentially associate withproteins less likely to illicit harmful blood clots such as albumin.FIGS. 13 and 14 highlight this principle.

FIG. 13 shows plasma proteins 1361 and interstices 1365 of a surface1371 with a Ra of 800 nanometers. Because of the interstices 1365 arerelatively larger than the plasma proteins 1361, the plasma proteins1361 can easily get lodged and grip the surface 1371. In instances wherethe plasma protein is, for example, fibrinogen, adherence or associationof the protein may result in thrombus formation.

FIG. 14 shows plasma proteins 1461 and interstices 1465 of a surface1471 with a Ra of 50 nanometers. Because of the interstices 1465 arerelatively smaller than plasma proteins 1461, the plasma proteins 1461,such as fibrinogen, find it more difficult to anchor onto the surface1471. If the surface chemistry is benign then this effect may be evenmore pronounced. Thus, it is evident that plasma proteins can moreeasily anchor to the interstices of the 800 nanometer surface (FIG. 13)whereas the 50 nanometer surface does not promote anchoring of plasmaproteins in surface interstices.

Table 1, below, presents information relating to blood proteins andthrombosis.

Plasma Percentage of Molecular Protein Plasma Proteins size (kDa)Dimensions (approx.) Albumin 55% 65 7.5 × 6.5 × 4.0 nm Alt Ref 15 × 3.8nm Globulins 38% 1,193 32 × 4 nm (all) Unreported γ-Globulin Fibrinogen 7% 340 Rod shaped 47.5 × 9 nm, or 90 × 3 nm Von Small amounts 500 toUnreported Willebrands 20,000 Factor

These data show albumin is abundant and relatively small in size,whereas fibrinogen is less abundant and much larger in size. Since,fibrinogen adsorption can cause formation of blood clots, cages andimpellers having surface textures within the scope of this disclosuremay comprise a roughness profile with interstices too small for aprotein as large as fibrinogen to adhere, but may, in some instances,allow smaller proteins such as albumin to adhere. Since albumin is notassociated with blood clots, it may be advantageous to permit thebinding of albumin, as the presence of harmless blood proteins such asalbumin may further prevent (for example, by steric hindrance)associations with blood proteins that may illicit harmful blood clots.Thus, the invention may provide a surface texture in which intersticesof the surface are too small for fibrinogen to adhere, but in someinstances, may allow smaller abundant proteins such as albumin toadhere.

In addition, there are a number of globulins in blood plasma includingγ-globulin which is relevant in thrombosis. The globulin γ-globulin isrelatively large with a 32 nanometer max linear dimension. Preferably,interstices present on cages and impellers of the disclosure are toosmall for γ-globulin to be adsorbed onto the surface. Von Willebrandsfactor is much less abundant protein but an important protein inthrombus formation. This protein is large and is broken up into smallerfunctional proteins by shear stress. It is thus difficult to call out adimension for this protein as its size is environment dependent.Although, within preferred embodiments, surfaces of cages and/orimpellers may comprise a roughness profile with interstices that are toosmall for a von Willebrands factor to adhere.

FIG. 15 shows a metal substrate 1501 with a modified surface chemistry1507. The modified surface chemistry 1507, as described above, may bedesigned to attract and bind with water molecules 1509. The binding ofwater molecules 1509 to the modified surface 1507 may form a barrierlayer 1511 that prevents the adsorption of plasma proteins 1515 andplatelets 1513 onto the surface. Such a design may prevent or reduceincidents of blood clot formation.

Specifically, catheters of the invention can include a metal interface1500 disposed between a metal substrate 1501 and blood 1516. The metalinterface 1500 (sometimes referred to as the metallic interface) relatesto surfaces of catheters that, when positioned inside a blood vessel,are in contact with blood. The metal interface 1500 can include asurface layer or layers, e.g., layers of modified surface chemistry1507, that interface between the metal substrate 1501 and blood.Illustrated are two important components of blood, plasma proteins 1515and platelets 1513.

The adsorption of plasma proteins 1515 generally onto the surface ofmedical devices happens immediately on contact with blood. This plays animportant role in how the body responds to the surface 1500 of themedical device over time. Plasma protein adsorption is a phenomenonwhereby a thin film of plasma proteins is laid onto the surface of asubstrate. Since over 100 plasma proteins have been identified to dateit will be appreciated that any given surface or any given segment of asurface can precipitate its own unique plasma protein response.Non-thrombogenic surfaces of the invention adsorb proteins orcombinations of proteins that mark these surfaces as more benign whereasthrombogenic surfaces adsorb proteins or combinations of proteins thatmark these surfaces as more foreign. Platelets 1513 are multifunctionalblood cells and they play a central role in the development of thrombus.

According to one preferred embodiment, the modified surface chemistry1507 is designed such that the surface can generate a benign responsefrom plasma proteins. In another embodiment, the modified surfacechemistry 1507 is designed to attract benign plasma proteins likealbumin. In yet another embodiment the modified surface chemistry 1507is established such that the surface can bind to water so as to preventplasma protein adsorption onto the metal interface 1500.

The modified surface chemistry 1507 can involve an enhanced oxide layer.The enhanced oxide layer may include a passivation of the surface 1500.The enhanced oxide layer may involve the exclusion or removal ofundesirable oxides from the surface. Undesirable oxides can be removedthrough electropolishing, for example. The enhanced oxide layer mayinvolve a modification of a spontaneously formed oxide layer to increasethe hydrophilicity of the layer.

The modified surface chemistry 1507 may include a first layer 1520 and asecond layer 1521, the second layer 1521 being disposed or laid down ontop of the first layer 1520. In this embodiment the first layer 1520 caninclude an oxide film extending over the metal surface 1500, e.g., themetallic interface of the cage 1013 and/or impeller 939. The secondlayer 1521 may include a polymer layer 1522. The polymer layer 1522 mayinclude a hydrophilic polymer. The polymer layer 1522 can have ahydrophilic polymer with a thickness of less than 5,000 nanometers, forexample, 4,000, or 3,000, or 2,000 nanometers. A reduced polymerthickness can be useful to minimize or prevent instances of mechanicalinterference, especially when polymer 1522 is disposed in the gap regionbetween the cage and the rotating impeller. In one embodiment thepolymer layer 1522 is formulated for binding to water molecules. Theability of the polymer layer 1522 to bind to water can be measured usinga contact angle measurement, as known in the art. Preferably the polymerlayer 1522 generates a water contact angle of less than 20 degrees. Inanother embodiment the polymer layer 1522 is configured to generate awater contact angle of less than 10 degrees.

In one embodiment the polymer layer 1522 can include a plurality ofpolymer chains 1523. The plurality of polymer chains 1523 each having ahydrophilic end 1524 and a binding end 1525. The binding end 1525 isformulated to bond to the first layer 1520 of modified surface chemistry1506 and the hydrophilic end 1524 is designed to interact strongly withwater molecules. In one embodiment the binding end 1525 of the pluralityof polymer chains 1523 is hydrophobic. In one embodiment the binding end1525 of the plurality of polymer chains 1523 is designed to establishstrong van der Waals attractive forces with said first layer 1520.

In one embodiment the binding end 1525 of the plurality of polymerchains 1523 is designed to establish strong polar attractive forces withsaid first layer 1520. In one embodiment the binding end 1525 of theplurality of polymer chains 1523 is designed to establish strong van derWaals and polar attractive forces with the first layer 1520. The strongintermolecular attractive forces of the binding region 1525 of thepolymer chains 1523 binds the unbound hydrophilic end 1524 to the firstlayer 1520. The unbound hydrophilic chain ends 1524 are designed to beindependent of each other. In one variation the unbound hydrophilicchain ends 1524 includes a linear polymer. In another variation, theunbound hydrophilic chain ends 1524 includes a branched polymer. In oneembodiment, the binding end 1525 of the plurality of chains 1523includes a plurality of linear polymer chains. In another embodiment,the binding end 1525 of the plurality of chains 1523 is designed tointerpenetrate with adjacent binding chain ends.

The plurality of polymer chains 1523 can include a block copolymer inanother embodiment with one block having a hydrophilic bock and thesecond block having a binding block.

In one embodiment the polymer layer 1522 includes a phosphorylcholinepolymer. In another embodiment, the polymer layer 1522 includes apolyethylene oxide polymer. In another embodiment, the polymer layer1522 includes a polyethylene succinate polymer. In another embodiment,the polymer layer 1522 includes a polyethylene adipate polymer. Inanother embodiment, the polymer layer 1522 includes a poly(vinylalcohol-co-ethylene) polymer. In another embodiment, the polymer layer1522 includes a polyacrylic acid polymer. It will be appreciated thatbased on the above disclosure that the polymer layer 1522 may includemixtures or copolymers of the aforementioned polymers or blockcopolymers or other polymers, such as hydrophobic polymers commonly usedin the art.

FIG. 16 shows a subset of elements in the periodic table withelectronegativity (EN) values below each element. For example, hydrogenhas an EN value of 2.2. Aspects of this disclosure provide a surface ofa catheter with a modified surface chemistry. The modified surfacechemistry may comprise atom pairs with an EN difference of at least 0.8,and preferably at least 1.2, or greater. For example, the modifiedsurface chemistry may have a high concentration of hydroxyl (—OH)groups. The difference between the EN values for H and O is[3.44-2.2=1.24]. A modified surface chemistry that is rich in atom pairswith an EN difference of 1.24 will confer hydrophilic properties to thesurface of the metal. Accordingly, elements preferred for use withcatheters of the invention are identified by dark circles 1603. Thegreater the concentration of hydroxyl groups, or atom pairs with similarEN differences on the surface, the more strongly water will compete (anddisplace) plasma proteins for adsorption onto the surface. Watersuccessfully displacing plasma proteins on the surface pacifies thesurface in terms of thrombus formation—even in high shear conditions orconditions of recirculation or conditions of blood stasis.

FIG. 17 shows a schematic stress strain curve for an elastomer suitablefor making an expandable member according to aspects of the invention.The top curve 1750 represents the stress strain curve for the elastomeras it is stretched in tensile. The lower curve 1760 is the stress straincurve for the elastomer as it is allowed to relax from a max test strain1770. The area between the two curves (Area A) is a measure of theenergy loss in the cycle of stretching and then un-stretching thematerial. The hysteresis loss ratio is the ratio of area A divided byareas A+B all expressed as a percentage. Where the percentage hysteresisloss ratio is low then the material will have desirable recoverycharacteristics. In preferred embodiments, expandable members of theinvention will comprise elastomers having low hysteresis loss ratios.

FIG. 18 shows an exemplary impeller assembly 1800 comprising a cage 1817with an expandable member 1807 attached to an outer surface in acollapsed state. The impeller assembly 1800 includes an atraumatic tip1801 at a distal end. At a proximal end, the impeller assembly 1800 isconnected to a catheter shaft 1819. The impeller assembly 1800 furtherincludes a distal interstitial surface 1805 and a proximal interstitialsurface 1809. The distal and proximal interstitial surfaces 1805, 1809are disposed underneath the expandable member 1807 and may providesurfaces for attachment of the expandable member 1807.

In some instances, the atraumatic tip involves a bull nosed tip. Forexample, the tip may be approximately 3.0±1.0 mm in length having afull-spherical radius of curvature, similar to a bull-nose shape. Thebull-nosed tip can be made of, for example, approximately 30-40durometer polyether block amide loaded with a radiopaque material forimproved visualization on a radiograph during insertion. The atraumatictip may include a metallic tip, for example, the tip may include themetal of the cage. The atraumatic tip comprises a polymer tip. Thepolymer tip may include an elongate flexible member. The polymer tip mayinclude a pig tail, i.e., a pig-tail shaped end. The atraumatic tip mayinclude an elongate member of increasing flexibility.

FIG. 19 shows an exemplary impeller assembly 1900 comprising a cage 1917with an expandable member 1907 attached to an outer surface. Theexpandable member 1907 is illustrated in an expanded configuration.

FIG. 20 shows an alternative embodiment of an expandable member 2007attached to an impeller assembly 2000. In this embodiment, theexpandable member 2007 folds into the collapsed state. The expandablemember 2007 comprising a fold 2009 is shown.

FIG. 21 shows an expandable member 2107. The expandable member 2107 isshown in an as formed state before it is collapsed for delivery.

FIG. 22 shows a surface roughness characterization of a portion of acage onto which a membrane may be attached. The surface is preferably aninterstitial surface. The membrane may comprise a portion of anexpandable member and/or facilitate the attachment of the expandablemember to the cage. The roughness may provide a multiplicity ofasperities and/or a plurality of interstices for attachment of themembrane. Attachment may comprise interpenetration of some of thematerial of the membrane around the asperities of the interstitialsurface and into the interstices of the interstitial surfaces. Thesurface has a Ra value of 3 micrometers when measured using a laserscanning microscope. Preferably, the surface onto which the membraneand/or expandable member attaches comprises a Ra value of at least 1micrometer, for example, 3 micrometers.

FIG. 23 shows a surface roughness characterization of a portion of acage onto which a membrane may be attached. The membrane may comprise aportion of an expandable member and/or facilitate the attachment of theexpandable member to the cage. The surface has a Ra value of 9micrometers when measured using a laser scanning microscope.

FIG. 24 shows a standard microscopy image of a surface of a cage 2513.An interstitial area 2510 of the surface is shown between highlypolished blood contacting surfaces 2540. The interstitial area 2510preferably comprises a roughness characterized by a Ra value of between1 and 10 micrometers. The roughness facilitates the attachment of anexpandable member.

FIG. 25 shows a portion of the periodic table of elements. 2501 refersto the period 4 transition metals. 2511 identifies a group of preferredelements for use with catheters of the invention. This group of metalsstarts with scandium at 21 on the periodic table and ends with zinc at30 on the periodic table. 2507 refers to the entire group of transitionmetals from group 3 to group 12 of the periodic table. 2509 refers toperiod 5 and 6 of the table.

FIG. 26 illustrates a cross sectional view of a portion of a metallicbody comprising a cage or an impeller. The metallic body 2601 includes asurface chemistry that offers non-thrombogenic properties. The surfacechemistry may comprise a surface film 2605. The metallic body 2601 has ametallic structure that is preferably a crystalline structure, forexample, of titanium 2607. Preferably, the surface film 2605 comprises athin surface layer comprising an oxide with at least one of the metallicelements of the metallic body 2601. For example, as shown in FIG. 26,the metallic body 2601 comprises titanium and the oxide film alsocomprises titanium. In another embodiment the surface film 2650comprises a thin surface layer composed of a first metal oxide and asecond metal oxide. In one variation of this embodiment the first metaloxide comprises a titanium oxide and the second metal oxide comprises analuminum oxide. In another variation of this embodiment the first metaloxide comprises a chromium oxide and the second metal oxide comprises anickel oxide. In another variation of this embodiment the first metaloxide comprises a chromium oxide and the second metal oxide comprises acobalt oxide.

FIG. 27 shows a schematic of a lattice structure 2700 of a surface film2705. The surface film 2705 is a titanium oxide film. It will beappreciated that a number of other oxide films are possible includingchromium oxide and aluminum oxide. In at least one embodiment, thelattice structure comprises a reutile-like lattice structure. Rutile isa mineral composed primarily of titanium dioxide (TiO₂), and is the mostcommon natural form of TiO₂. Other polymorphs of TiO₂ may also be used,including anatase, akaogiite, and brookite.

In one aspect, the invention provides an intravascular device includinga catheter dimensioned for insertion into a vein. The catheter having aproximal portion and a distal portion and a cage attached to the distalportion of the catheter, the cage housing an impeller. At least aportion of the surface of the cage or the impeller having anon-thrombogenic metallic interface. The non-thrombogenic metallicsurface includes non-thrombogenic metals, as discussed herein, which areintended to be in contact with blood when the catheter is in use insidethe vein.

The non-thrombogenic metallic interface may be a metal oxide film. Themetal oxide film being formulated to confer or enhance non-thrombogenicproperties of a metal of the catheter. The metal oxide film may includean oxygen active material, which is a material that spontaneously formsan oxide when exposed to oxygen without the need for a catalyst tofacilitate the reaction. The oxygen active material can be a materialthat spontaneously forms an oxide when exposed to air or an atmospherewith a similar oxygen content to air.

The non-thrombogenic metallic interface may include a coating. Thecoating may be a metal oxide film. The metal oxide film can includehydrophilic groups that attract water molecules from blood, therebydisplacing blood proteins associated with thrombosis formation. In someinstances, the attachment of hydrophilic groups comprises a chemicalmodification of the oxide film. The attachment of hydrophilic groups caninclude a chemical attraction, an ionic attraction or a covalent bond.

The non-thrombogenic metallic interface may include a coating. Thecoating may include a hydrophilic coating. The hydrophilic coating caninvolve a plurality of polymer chains. The plurality of polymer chainsmay include a hydrophilic region and a substrate attachment region. Thesubstrate attachment region may include at least one chemical functionalgroup designed to bond with a metal surface or a metal oxide surface.The substrate attachment region may include a plurality of functionalgroups that in unison bond to the metal surface or metal oxide surface.The plurality of functional groups may include a polymer chain. Theplurality of functional groups may include a hydrophobic polymer chain.The plurality of functional groups may include a triol. The triol mayinclude a chain end of a hydrophilic polymer chain. The triol comprisesa R-1,1,1 triol. The plurality of functional groups may include asilane. The plurality of functional groups may include an acrylic. Thesubstrate attachment region may include a reactive chain end where saidreactive chain end is reactive to a metal or metal oxide substrate.

The coating thickness is preferably small in comparison to the gapbetween the impeller and the cage. For example, the coating thicknesscan be less than 20% of the gap between the impeller and the cage. Thecoating thickness can be less than 10% of the gap between the impellerand the gage. The coating thickness can be less than 5% of the gapbetween the impeller and the gage. The coating thickness can be lessthan 2% of the gap between the impeller and the gage.

FIG. 28 shows a triol coupling agent 2800. The triol coupling agentincludes alcohol functional groups concentrated on one region of thecoupling agent. The triol coupling agent can be included in a coating ofa catheter to enhance antithrombogenic properties. In some instances,the triol may be one of a plurality of functional groups useful forattaching a non-thrombogenic coating to a metal surface or metal oxidesurface of the catheter.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification, and guidance that can be adapted to the practice ofthis invention in its various embodiments and equivalents thereof.

1. An intravascular device, the device comprising: a catheterdimensioned for insertion into a vein, the catheter comprising aproximal portion and a distal portion; and a cage attached to the distalportion of the catheter, the cage housing an impeller, wherein at leasta portion of the cage or the impeller comprises a modified surfacechemistry that minimizes or prevents formation of blood clots.
 2. Thedevice of claim 1, wherein the modified surface chemistry comprises ahydrophilic surface.
 3. The device of claim 2, wherein the hydrophilicsurface is configured to allow blood water to outcompete blood proteinsfor adhesion with the surface when the catheter is inserted into thevein. 4-6. (canceled)
 7. The device of claim 2, wherein the hydrophilicsurface comprises a water contact angle of 20 degrees or less.
 8. Thedevice of claim 7, wherein the hydrophilic surface comprises a watercontact angle of 10 degrees or less.
 9. The device of claim 1, whereinthe modified surface chemistry comprises a super-hydrophilic surface.10-11. (canceled)
 12. The device of claim 1, wherein the cage and/orimpeller comprises a metal and the modified surface chemistry of thecage and/or the impeller comprises a modification to an oxide layer ofthe metal.
 13. The device of claim 12, wherein the metal comprises atransition metal from period 4, D-block of the periodic table and theoxide layer comprises an oxide of said period 4 transition metals. 14.(canceled)
 15. The device of claim 1, wherein the cage and/or impellercomprise a surface layer and the surface layer comprises an enrichedconcentration of titanium or chromium. 16-18. (canceled)
 19. The deviceof claim 1, wherein the modified surface chemistry comprises a coating.20. The device of claim 19, wherein the coating comprises a coatingthickness and the coating thickness is greater than the averageroughness (Ra) of the surface of the cage and impeller.
 21. The deviceof claim 19, wherein the coating comprises at least one of apolysaccharide, a polymer, or a hydrogel.
 22. (canceled)
 23. The deviceof claim 21, wherein the polysaccharide comprises heparin.
 24. Thedevice of claim 1, wherein the modified surface chemistry comprises analtered oxide layer.
 25. The device of claim 24, wherein the oxide layeris formed by electropolishing, heat treatment, or acid passivation.26-28. (canceled)
 29. The device of claim 1, wherein the cage comprisesthe modified surface chemistry.
 30. The device of claim 1, whereinsubstantially all of the cage and/or the impeller that is exposed toblood when the catheter is operating inside the vein comprises themodified surface chemistry. 31-32. (canceled)
 33. The device of claim 1,wherein a distal portion of a shaft of the impeller and a distal portionof the cage defines a gap.
 34. The device of claim 33, wherein at leastone of the distal portion of the shaft or the distal portion of the cagedefining the gap comprises the modified surface chemistry. 35-39.(canceled)
 40. The device of claim 1, wherein the modified surfacechemistry comprises a modification to an oxide layer and the thicknessof said modification is less than 5,000 picometers. 41-48. (canceled)